Annals of Oncology 12 (Suppl. I): S3-S8, 2001.

2001 Kluwer Academic Publishers. Primed in the Netherlands.

Symposium article
The basic biology of HER2
I. Rubin & Y. Yarden
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel

Summary

Introduction

The neu gene was originally identified in rat neuroectodermal tumors [1] and later its close human relative was
isolated. This human gene encodes a protein that has a
structure consistent with a growth factor receptor and
has been designated HER2, due to its similarity to the
human epidermal growth factor receptor [2, 3]. The
HER2 receptor has an important role in normal cell
growth and differentiation. However, amplification of
the HER2 gene leads to overexpression of the receptor,
which is linked to the development of many types of
human cancers including breast, ovarian and those of
the gastrointestinal tract [4, 5].
Breast cancer is a leading cause of cancer-related
death in women. In many cases, the cancer is resistant
to conventional drugs, resulting in treatment failure.
The prognosis for patients with breast cancer is determined by well-recognized pathologic features associated
with aggressiveness, histologic grade, tumor size and
nodal involvement. Approximately 20%-30% of breast
cancers overexpress the HER2 receptor, and it is now
recognized that high levels of HER2-receptor expression
are an indicator of poor prognosis in patients with
breast cancer. Furthermore, overexpression of HER2 is
associated with aggressive tumor growth and metastatic
activity [4]. Slamon et al. [6] first observed that HER2gene amplification independently predicted overall (OS)
and disease-free survival (DFS) and these findings have

Key words: breast cancer, HER2 (erbB-2, neu), network,

signal transduction, tumor growth, tyrosine phosphorylation

been confirmed by subsequent studies [7]. These patients

have poor response rates and short DFS and OS compared with women whose tumors do not overexpress this
receptor.
There have been attempts to use HER2 status as a
predictive factor for response to hormonal and chemotherapy in breast cancer. Although the presence
of estrogen receptors indicates response to hormonal
therapy, HER2 overexpression is associated with poor
response to tamoxifen, possibly because of different
growth-signaling pathways. In contrast, HER2 overexpression may be associated with a better response to
chemotherapy, particularly anthracyclines, than expected.
Therefore, HER2 status is now a well-characterized
indicator of aggressiveness and poor prognosis. Moreover, HER2 is being investigated as a target for new
breast cancer treatments. Monoclonal antibodies directed
against the HER2 receptor are currently the most promising treatments. It is important to understand the biology
of the receptor in order to elucidate the mechanism of
action of these newly-developed treatments.
The HER family of receptors
The HER/erbB signaling network has developed in
parallel with the evolution of complex life forms. The
ancestors of HER receptors may be seen in invertebrate
organisms such as Caenorhabiditis elegans (C. elegans)

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

Human epidermal growth factor receptors (HER/erbB)

constitute a family of four cell surface receptors involved in
transmission of signals controlling normal cell growth and
differentiation. A range of growth factors serve as ligands, but
none is specific for the HER2 receptor. HER receptors exist as
both monomers and dimers, either homo- or heterodimers.
Ligand binding to HER1, HER3 or HER4 induces rapid
receptor dimerization, with a marked preference for HER2 as
a dimer partner. Moreover, HER2-containing heterodimers
generate intracellular signals that are significantly stronger
than signals emanating from other HER combinations. In
normal cells, few HER2 molecules exist at the cell surface, so
few heterodimers are formed and growth signals are relatively

weak and controllable. When HER2 is overexpressed multiple

HER2 heterodimers are formed and cell signaling is stronger,
resulting in enhanced responsiveness to growth factors and
malignant growth. This explains why HER2 overexpression is
an indicator of poor prognosis in breast tumors and may be
predictive of response to treatment. HER2 is a highly specific
and promising target for new breast cancer treatments.
The recombinant human anti-HER2 monoclonal antibody
(rhuMAb-HER2, trastuzumab, Herceptin) induces rapid removal of HER2 from the cell surface, thereby reducing its
availability to heterodimers and reducing oncogenicity.

Extracellular domain
(632 amino acids)
Ligand-binding site

High affinity/
narrow specificity

Low affinity/
broad specificity

Intracellular domain
(580 amino acids)
Tyrosme kinase activity
Cytoplasm

Figure I. Structure of the HER2 protein and its transmembrane

topology.

NDF-p: erf>B-4>erbB-3
TGF-a: e/fcB-1

ert>B-2>ert>B-4=erbB-3>ert>B-1
ert>B-2>ert>B-1>erfjB-4>ert>B-3

Figure 2. Bivalence of EGF-like ligands. The model refers to

neuregulin-1 and is based on results described in Tzahar et al. [19],
(Reproduced by permission of Elsevier Science from Tzahar and
Yarden [8].)

HER2 is a co-receptor for many different ligands and

is often transactivated by EGF-like ligands, resulting in
the formation of HER1-HER2 heterodimers [12, 13].
Neuregulins can induce the formation of HER2-HER3
and HER2-HER4 heterodimers [11, 14-16]. However,
no known ligand can promote the HER2 homodimer
(HER2-HER2), suggesting that no existing ligand
binds directly to HER2. In support of this theory,
analysis of representative pox virus growth factors,
HER ligands of viral origin, revealed that none bind
directly to HER2, but all are able to recruit HER2 into
heterodimers [17]. This observation led us to propose
that HER2 functions as a ligand-less receptor for many,
if not all, HER ligands [18].
Inter-receptor interactions within the HER family
are not random. Instead, there is a distinct hierarchy
that prefers HER2 as an interaction partner [16]. An
examination of the structure of one of the ligands helps
Ligands of HER receptors
to explain this preference. Neuregulin-1 (NDF) seems to
An understanding of the action of ligands of HER be a bivalent molecule with two binding sites for HER
receptors is crucial to understanding the role of the receptors: a high affinity/narrow specificity site (Nreceptors themselves. The HER receptors exist as mono- terminal) and a low affinity with broad specificity site
mers. However, on ligand binding they form receptor (C-terminal) [19]. The high affinity site binds first to its
dimers, which can either be homodimers with the same specific site (HER3 or HER4 receptor). Once the low
receptor type (e.g., HER1-HER1) or heterodimers with affinity site is effectively 'immobilized' at the plasma
different receptor types (e.g., HER1-HER2) [10], Dimer membrane, its operational affinity to potential partners
formation is driven by the higher stability of the com- of the dimer is increased. Importantly, the receptor that
plex formed between a ligand and two receptors com- preferentially binds to the immobilized low affinity arm
of the ligand is HER2 (Figure 2). As a result of
pared with the monomeric receptor.
The HER1 receptor has many roles and is activated this heterodimerization, the HER2 receptor is able to
by six ligands: epidermal growth factor (EGF), trans- participate in signal transduction in the absence of a
forming growth factor a (TGFa), amphiregulin, hepa- specific ligand. This preferential binding with HER2 is
rin-binding EGF-like growth factor, betacellulin and also enhanced by the overexpression of HER2 in human
epiregulin. HER3 and HER4 receptors bind neuregulins cancer cells [8].
(NGFs), a family of structurally diverse peptides [10].
Heterodimers generate more potent signals than
Signaling by all neuregulins is directed through mitogen- homodimers, and those containing HER2 have a particactivated protein kinase (MAPK) [11].
ularly high ligand binding and signaling potency com-

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

and Drosophila melanogaster. These organisms only

have one HER receptor. Although the receptor in
C. elegans has one ligand, the receptor in fruit flies
{Drosophila melanogaster) has four ligands. In contrast,
the mammalian HER receptor family comprises four
closely-related growth factor receptors that show a high
degree of homology with each other. The receptors are
all located on the cell membrane and are found in a
variety of tissues. They interact with a range of ligands,
all sharing an EGF-like motif of 50-55 amino acids,
including six highly conserved cysteine residues [8].
The HER2 receptor is encoded by the HER2 gene, a
proto-oncogene mapped to chromosome 17q21 [2]. The
HER2 receptor is a 1255 amino acid, 185kD transmembrane glycoprotein also designated as pl85 HER [2].
All four HER receptors comprise a cysteine-rich
extracellular ligand binding site, a transmembrane
lipophilic segment, and an intracellular domain with
tyrosine kinase catalytic activity (Figure 1) [9]. A terminal carboxyl autophosphorylation segment is most
likely to be responsible for translation of the activation
signals initiated by extracellular ligand binding into
physiologic action.

oo oo oo
Proliferation
index

3.2

5.0

3.1

o o
3.1

6.5

10.5

Figure 3 Relative potency of HER dimers. Note that H ER4-containing combinations were omitted. The mitogenic index of each HER dimer was
calculated on the basis of experiments described in Pinkas-Kramarski et al. [12]. (Reproduced by permission of Oxford University Press from
Pinkas-Kramarski et al. [12].)
ert>B-1

e/6B-1T3

erbB-3

EC

TK

CT

Signal

No signal

Figure 4. HER1-HER3 chimera is more potent than any other

receptor combination. The presented erb-lT3 artificial fusion protein
was designed and tested in animal cells. Its activity exceeded that of the
HER2-HER3 combination. (Reproduced by permission of Oxford
University Press from Waterman et al. [24].)

Negative regulation of HER receptors and its relevance

to cancer immunotherapy

Of the 10 different HER homo- and heterodimer combinations, those containing HER2 are long-lived and
pared with hetero- and homodimers without HER2 [20, transmit strong signals, and are thus associated with
21]. The increased potency of HER2-containing hetero- malignant growth (Figure 5) [5]. As mentioned earlier,
dimers is attributable to two reasons: first, the hetero- overexpression of HER2 promotes the formation of
dimers are characterized by a relatively slow rate of more HER2 heterodimers. By contrast, the non-HER2
ligand dissociation [10], and second, unlike HER1 whose combinations signal relatively weakly. This signaling
rate of ligand-induced endocytosis is rapid, HER2 is a is normal, and these combinations are essential for
slowly internalizing receptor [12, 22]. Thus, signaling by normal cell growth but will not lead to tumor growth
HER2-containing receptor combinations is relatively (Figure 5) [5].
prolonged and results in enhanced activation of signalIn mice carrying human tumor cells overexpressing
ing pathways such as the MAPK route. The most potent a rodent oncogenic mutant of HER2, the growth of
heterodimer is HER2-HER3 (Figure 3). This combina- tumors was inhibited by monoclonal antibodies directed
tion is the most mitogenic and HER3 is the predom- at the HER2 receptor [25]. Tumor regression can be
inant partner of HER2 in carcinoma cells [10, 11]. This demonstrated also in a cell system that overexpresses
demonstrates how heterodimerization can be used to the human HER2. When a number of different anticontrol cell activity. The HER 3 receptor has only a bodies to HER2 were examined, the rate of tumor
weakly active kinase domain [23] and HER3 homo- regression depended on type of antibody; some antidimers are completely inactive [12]. However, HER3 bodies almost completely inhibited tumor growth, while
has many binding sites for signaling proteins and it is others were only partial antagonists [26]. However,
possible that an active kinase with so many binding sites enhancement of growth also occurred upon treatment
would be harmful to the cell, so control is maintained by of cells with certain monoclonal antibodies. In these latter
formation of the heterodimer requiring both a ligand for cases, labeling of tumor cells or the antibodies revealed
HER3 and the HER2 partner. This hypothesis was that the tumor inhibitory antibodies were not processed
tested using a chimeric receptor comprised of the kinase by the tumor cells. By contrast, tumor-inhibitory antidomain of HER1 fused to the signaling domain of HER3 bodies were rapidly internalized and metabolized by

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

TM
JM

[24]. As predicted, this engineered HER1-HER3 chimera

was more active than any other HER protein or HER
combination (Figure 4).
In conclusion, signal transduction by the HER family
may be considered in terms of information processing
by networks. The network is a layered organization of
units. Thus, the HER network consists of an input layer
(ligands, growth factors), information processing layer
(receptors, SH2-proteins, transcription factors), and an
output layer (cell growth, differentiation or migration).
Thus, receptor dimerization is important as it allows a
signaling network with an enormous potential for diversification of biologic messages instead of four receptors
with only four linear pathways. In effect, HER2 may be
considered as a master regulator of the network because
it promotes and controls signaling.

EGF-like ligands
(>30)
erbB dimers
(10 types)

SH2/PTB
adaptors
(e.g., Src, She)
Enzyme
cascades
(e.g.MAPK.JNK)

Malignant
growth
Figure 5. The HER signaling network. The layered structure of the HER signaling network is presented. Numbers refer to the four HER proteins.
Note that HER3 carries an inactive catalytic domain. (Reproduced with permission from Klapper et al. [5].)

cancer cells overexpressing HER2 [27]. These observations led us to suggest that tumor inhibition is due to the
endocytic removal of HER2 from the cell surface [5].
Consistent with this model, combining two distinct antibodies to HER2 better inhibits tumors than each antibody alone, probably because the combination leads to
accelerated degradation of HER2 inside tumor cells
[28]. In conclusion, the anti-tumor effect of HER2specific antibodies is due to the ability of certain antibodies to accelerate internalization and degradation of
the oncoprotein.
The attribution of immunotherapy to enhanced endocytosis focused the interest on processes leading to
HER2 degradation. Generally, HER receptors are continuously recycled back to the cell surface after endocytosis through endosomes. Alternatively, the receptor
may be degraded after passing from endosome to lysosome. The recycling/degradation pathway is controlled
through an adaptor molecule, c-Cbl, which is a major
tyrosine phosphorylation substrate of HER [29]. c-Cbl
is the normal form of this sorting molecule and is
needed for the HER1 receptor to move from endosome
to lysosome and thus be degraded [30]. Unlike HER1,
which is strongly coupled to c-Cbl, HER2 only weakly
interacts with the adaptor, but the two neuregulin
receptors, HER3 and HER4, do not recruit c-Cbl [31].
The biochemical basis of c-Cbl's action has been recently resolved. The ring finger domain of c-Cbl, a motif
detected in two oncogenic forms of c-Cbl, serves as a
binding site for a ubiquitin processing enzyme (E2).

Thereby, when c-Cbl is recruited to a specific tyrosine

phosphorylated residue of HER1, it enhances polyubiquitination of the receptor (Figure 6). Polyubiquitin
tracts are sufficient for targeting HER1 to proteasomal
and lysosomal degradation [32]. It should be noted that
HER3 is continuously recycled [33] because is does not
have an active kinase domain, nor does it carry a c-Cbl
docking site. Our most recent results suggest that antitumor antibodies tag the HER2 receptor to degradation
by recruiting c-Cbl and enhance ubiquitination of HER2.

Conclusions: Implications of HER2 biology for the

treatment of breast cancer

In conclusion, the HER2 gene and HER2 receptor play

a crucial role in the network of cell-signaling processes
controlling normal growth and development. The HER
family binds a range of ligands, and although HER2
does not bind a specific ligand, it is the preferred partner
for receptor dimerization and this enables it to perform
its role through growth factor binding at its partner
receptor.
The role of HER2 in cell growth can be summarized
in simple terms. When HER2 is normally expressed,
ligands that bind to the HER receptors form only a few
HER2 heterodimers, and the responses to these growth
factors are relatively weak, resulting in normal growth
of cells. However, when HER2 is overexpressed as in
cancer cells, many ligands originating primarily in the

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

Transcription
factors
teg., Egr-1. Sp-1)

Transfection

Cont.

c-Cbl

ing breast tumors that overexpress HER2 have been

investigated, including tyrosine kinase inhibitors, antiEGF
sense approaches, designed to downregulate expression
of the HER2 gene, and immunization to actively boost
anti-HER2 responses. In addition, selective targeting
can be achieved using monoclonal antibodies directed
against the extracellular domain of the HER2 protein.
As HER2 is expressed only in low levels in normal tissue
IB Ab: anti Ub
[37], this permits a suitable therapeutic window to
minimize damage to normal cells.
A number of murine monoclonal antibodies directed
against the HER2 receptor have been developed. The
monoclonal antibodies inhibited tumor growth in laboratory model systems. The mechanism of action of their
anti-tumor effects is not yet completely understood
although, as suggested earlier in this paper, the monoclonal antibodies may direct HER2 towards a degradation pathway. However, the murine antibodies caused
IB Ab: anti erfjB-1
the development of neutralizing human anti-mouse antibodies (HAMA) and did not progress beyond experimental stages. Since these experiments, the murine 4D5
monoclonal antibody has been humanized [38], resultIP Ab: anti ert>B-1
ing in the recombinant human anti-HER2 monoclonal
Figure 6. c-Cbl controls HER degradation and recycling. Chinese
hamster ovary cells were transfected with plasmids directing the antibody (rhuMAb-HER2, trastuzumab, Herceptin).
expression of HER1. Some cells were transfected also with a c-Cbl This antibody is being introduced into clinical practice
expression vector. Following 40 hours, cells were treated with EGF for patients with metastatic breast cancer. It is not
(100 ng/ml) or left untreated for 10 minutes. Cell extracts were associated with the development of HAMA and was
examined by immunoprecipitation (IP) and immunoblotting (IB) with effective in phase II and III clinical trials. In addition to
the indicated antibodies. Closed arrowheads mark the location of the
being active as a single agent, trastuzumab potentiates
HERl/erfeB-1 protein band, and the open arrowhead marks the ubiqthe anti-tumor activity of paclitaxel and doxorubicin
uitinated protein.
[39] and cisplatin [40].
Therefore, monoclonal antibodies are the potential
stroma or in the tumor cells themselves will recruit greatest advance in the treatment of tumors overHER2 into heterodimers. The heterodimers stay longer expressing HER2. Elucidation of the role of HER2 in
at the cell surface, and their signaling is enhanced. cell growth should allow the mechanism of action of
This results in potent stroma-to-epithelium signaling, monoclonal antibodies to be determined and should
enhanced responsiveness to growth factors and, eventu- help optimize treatment of aggressive HER2-positive
ally, malignant growth.
tumors.
In breast cancers, 92% of cases of HER2 overexpression result from HER2-gene amplification (generation
of more than the normal two gene copies) [34]. This Acknowledgements
leads to increased transcription of the HER2 gene and
concomitant increased synthesis of HER2 protein. In Research in our laboratory is supported by the National
cancer cells, HER2 protein levels may be 100 times those Institutes of Health and the Israel Basic Research Fund.
in normal cells [35]. This is a consequence of gene
amplification and/or transcriptional alterations. Amplification is also the most common cause of overexpres- Note
sion in ovarian and gastric tumors [4]. The mechanism
of gene amplification has not been determined. How- Dr Yarden has reported that he is a consultant for Novartis and has
ever, the HER2 gene is not amplified in a few tumor received research support from Genentech, Inc.
types (lung, mesenchymal, bladder and esophageal)
overexpressing HER2 and, in these cases, overexpression
may result from transcriptional or post-transcriptional References
dysregulation [36].
1. Shih C, Padhy LC, Murray M,Weinberg RA. Transforming genes
As HER2 is frequently overexpressed in human tumors
of carcinomas and neuroblastomas introduced into mouse fibroand often confers a more aggressive clinical course,
blasts. Nature 1981; 290: 261-4.
HER2 is being investigated as a target for cancer therapy.
2. Coussens L, Yang-Feng TL, Liao Y-C et al. Tyrosine kinase
Its localization at the cell surface makes it an easy target
receptor with extensive homology to EGF receptor shares chroto access. A wide range of therapeutic strategies targetmosomal location with neu oncogene. Science 1985; 230: 1132-9.

II

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

24.

25.

26.

27.

28.

29.
30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

pl8OErbB3 possesses an impaired tyrosine kinase activity. Proc

Natl Acad Sci USA 1994; 91: 8132-6.
Waterman H, Alroy I, Strano S et al. The carboxyl terminus of the
kinase-defective neuregulin receptor ErbB-3 confers mitogenic
superiority and dictates endocytic routing. EMBO J 1999; 18:
3348-58.
Drebin JA, Link VC, Stern DF et al. Down-modulation of an
oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 1985; 41: 697-706.
Stancovski I, Hurwitz E, Leitner O et al. Mechanistic aspects of
the opposing effects of monoclonal antibodies to the ERBB2
receptor on tumor growth. Proc Natl Acad Sci USA 1991; 88:
8691-5.
Hurwitz E, Stancovski I, Sela M, Yarden Y. Suppression and
promotion of tumor growth by monoclonal antibodies to ErbB-2
differentially correlate with cellular uptake. Proc Natl Acad Sci
USA 1995; 92: 3353-7.
Kasprzyk PG, Song SU, Di Fiore PP, King CR. Therapy of an
animal model of human gastric cancer using a combination of
anti-erbB-2 monoclonal antibodies. Cancer Res 1992; 52: 2771-6.
Thien CBF, Langdon W. c-Cbl: A regulator of T-cell receptormediated signaling. Immunol Cell Biol 1998; 76: 473-82.
Levkowitz G, Waterman H, Zamir L et al. c-Cbl/Sli-1 regulates
endocytic sorting and ubiquitination of the epidermal growth
factor receptor. Genes Dev 1998; 12: 3663-74.
Levkowitz G, Klapper LN, Tzahar E et al. Coupling of the c-Cbl
protooncogene product to ErbB-1 /EGF-receptor but not to other
ErbB proteins. Oncogene 1996; 12: 1117-25.
Levkowitz G, Waterman H, Ettenberg SA et al. Ubiquitin ligase
activity and tyrosine phosphorylation underlie suppression of
growth factor signaling by c-Cbl /Sli-1. Mol Cell 1999; 4: 1029-40.
Waterman H, Sabanai I, Geiger B, Yarden Y. Alternative mtracellular routing of ErbB receptors may determine signaling
potency. J Biol Chem 1998; 273: 13819-27.
Pauletti G, Godolphin W, Press MF, Slamon DJ. Detection and
quantitation of HER-2/neu gene amplification in human breast
cancer archival material using fluorescence in situ hybridization.
Oncogene 1996; 13: 63-72.
Venter DJ, Tuzi NL, Kumar S, Gullick WJ. Overexpression of the
c-erbB-2 oncoprotein in human breast carcinomas: Immunohistological assessment correlates with gene amplification. Lancet
1987; ii: 69-72.
Slamon D, Godolphin W, Jones LA et al. Studies of the HER-2/
neu protooncogene in human breast and ovarian cancer. Science
1989; 244. 707-12.
De Potter CR, Schelfhout AM, Verbeeck P et al. Neu overexpression correlates with extent of disease in large-cell ductal in situ
carcinoma of the breast. Hum Pathol 1995; 26: 601-6.
Carter P, Presta L, Gorman CM et al. Humanization of the antipl85 H E R 2 antibody for human cancer therapy. Proc Natl Acad Sci
USA 1992; 89: 4285-9.
Baselga J, Norton L, Albanell J et al. Recombinant humanized
anti-HER2 antibody (Herceptin) enhances the antitumor
activity of paclitaxel and doxorubicin against HER2/e overexpressing human breast cancer xenografts. Cancer Res 1998; 58:
2825-31.
Pietras RJ, Fendly BM, Chazin VR et al. Antibody to HER-2/neu
receptor blocks DNA repair after cisplatin in human breast and
ovarian cancer cells. Oncogene 1994; 54: 1829-38.

Correspondence to
Y. Yarden, PhD
Department of Biological Regulation
The Weizmann Institute of Science
Rehovot 76100
Israel
E-mail: yosef.yarden@weizmann.ac.il

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2016

3. King CR, Kraus MH, Aaronson SA. Amplification of a novel

v-erAB-related gene in a human mammary carcinoma. Science
1985; 229: 974-6.
4. Hynes NE, Stern DF. The biology oferbB-2/neu/HER-2
and its
role in cancer. Biochem Biophys Acta Rev Cancer 1994; 1198:
165-84.
5. Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical
and clinical implications of the ErbB/HER signaling network of
growth factor receptors. In Klein G, Woude V (eds): Advances in
Cancer Research. New York: Academic Press 2000; 25-79.
6. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer:
Correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science 1987; 235: 177-82.
7. Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer:
Prognostic factor, predictive factor, and target for therapy. Stem
Cells 1998; 16: 413-28.
8. Tzahar E, Yarden Y. The ErbB-2/HER2 oncogenic receptor of
adenocarcinomas: From orphanhood to multiple stromal hgands.
BBA Rev Cancer 1998; 1377: M25-37.
9. van de Geer P, Hunter T, Lindberg RA. Receptor protein-kinases
and their signal transduction pathways. Annu Rev Cell Biol 1994;
10: 251-337.
10. Alroy I, Yarden Y. The ErbB signaling network in embryogenesis
and oncogenesis: Signal diversification through combinatorial
ligand-receptor interactions. FEBS Lett 1997; 410: 83-6.
11 Pinkas-Kramarski R, Shelly M, Guarino BC et al. ErbB tyrosine
kinases and the two neuregulin families constitute a ligandreceptor network. Mol Cell Biol 1998; 18: 6090-101.
12 Pinkas-Kramarski R, Soussan L, Waterman H et al. Diversification of Neu differentiation factor and epidermal growth factor
signaling by combinatorial receptor interactions. EMBO J 1996;
15: 2452-67.
13. Pinkas-Kramarski R, Eilam R, Alroy I et al. Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene
1997; 15: 2803-15.
14. Baly DL, Wirth CM, Allison DA et al. Development and characterization of a rhuMAb HER2 antibody assay for clinical evaluation of cytotoxic potency. Proc Am Assoc Cancer Res 1997; 38:
181A.
15. Burden S, Yarden Y. Neuregulins and their receptors: A versatile
signaling module in organogenesis and oncogenesis. Neuron
1997; 18: 847-55.
16. Tzahar E, Waterman H, Chen X et al. A hierarchical network of
interreceptor interactions determines signal transduction by Neu
differentiation factor/neuregulin and epidermal growth factor.
Mol Cell Biol 1996; 16: 5276-87.
17. Tzahar E, Guarino BC, Waterman H et al. Pathogenic poxviruses
reveal viral strategies to exploit the ErbB signaling network.
EMBOJ 1998; 17:5948-63.
18. Klapper LN, Glathe S, Vaisman N et al. The ErbB-2/HER2
oncoprotein of human carcinomas may function solely as a
shared coreceptor for multiple stroma-denved growth factors.
Proc Natl Acad Sci USA 1999; 96: 4995-5000.
19. Tzahar E, Pinkas-Kramarski R, Moyer JD et al. Bivalence of
EGF-like ligands drives the ErbB signaling network. EMBO J
1997; 16: 4938-50.
20. Karunagaren D, Tzahar E, Beerli RR et al. ErbB-2 is a common
auxiliary subunit of N D F and EGF receptors: Implications for
breast cancer. EMBOJ 1996; 15: 254-64.
21. Sliwkowski MX, Schaefer G, Akita RW et al. Coexpression of
erbB2 and erbB3 proteins reconstitutes a high affinity receptor for
heregulin. J Biol Chem 1994; 269: 14661-5.
22. Baulida J, Kraus MH, Alimandi M et al. All ErbB receptors other
than the epidermal growth factor receptor are endocytosis
impaired. J Biol Chem 1996; 271: 5251-7.
23. Guy PM. Platko JV, Cantley LC et al. Insect cell-expressed